Therapy For Metastatic Renal Cell Carcinoma Research Articles

MP64-17 THE ROLE OF 18-FDG PET/CT SCAN IN EARLY RESPONSE TO SYSTEMIC THERAPY FOR METASTATIC RENAL CELL CARCINOMA: BEYOND SUV max

You have accessJournal of UrologyCME1 Apr 2023MP64-17 THE ROLE OF 18-FDG PET/CT SCAN IN EARLY RESPONSE TO SYSTEMIC THERAPY FOR METASTATIC RENAL CELL CARCINOMA: BEYOND SUVmax Sanjoy Kumar Sureka, Sumit Mandal, and Uday Pratap Singh Sanjoy Kumar SurekaSanjoy Kumar Sureka More articles by this author , Sumit MandalSumit Mandal More articles by this author , and Uday Pratap SinghUday Pratap Singh More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003322.17AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: In metastatic renal cell carcinoma (RCC), the CECT scan evaluates lesions in their anatomic context while FDG-PET/CT scan demonstrates metabolic component. Often the size of the lesion may take time to respond and metabolic activity changes first. We evaluated the role of FDG PET/CT scan in this setting with an objective to evaluate the role of FDG-PET/CT as a monitoring tool for early response to systemic therapy in metastatic RCC. METHODS: From January 2017 to Dec 2021, 48 patients with synchronous and metachronous metastatic RCC with ECOG <2 underwent a baseline 18-FDG/PET-CT scan followed by repeat scan for response assessment 3 months later. Pregnant and nursing mothers, hypothyroid, diabetics and those with brain metastasis or another malignancy were excluded. Response evaluation was done with both RECIST version 1.1 (for CECT) and PERCIST (for PET-CT) criteria. Also, total lesion glycolysis (TLG), and metabolic tumour volume (MTV) were assessed. Interrater agreement was done using Cohen’s kappa between the scores. RESULTS: Mean age of 48 patients was 55.3±5.6 years and 28(58.3%) were males. Clear cell histology was present in 44 patients. Sunitinib, Pazopanib, Everolimus and Axitinib were given to 12, 22, 6 and 8 patients respectively. Out of 22 patients with partial response (PR) in RECIST, 8 patients were upgraded to Stable disease (SD) in 2 and Progressive disease (PD) in 6 as per PERCIST, subsequently leading to a change in their management. All 14 patients with PR in PERCIST had better long-term survival as compared to the rest upgraded 8. There was a significant decline in median SUVmax, MTV and TLG after 3 months in these patients. CONCLUSIONS: 18-FDG PET/CT scan is useful for monitoring the early response to systemic therapy in metastatic RCC based on 18-FDG avidity including TLG & MTV and correctly identifying partial responders. Changes in the metabolic parameters detect response to therapy earlier and guide subsequent changes in therapy. Source of Funding: None. © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e887 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sanjoy Kumar Sureka More articles by this author Sumit Mandal More articles by this author Uday Pratap Singh More articles by this author Expand All Advertisement PDF downloadLoading ...

Comparative Assessment of the Safety between Pazopanib and Sunitinib for Metastatic Renal Cell Carcinoma

Renal cell carcinoma (RCC) is the most common kidney lesion with approximately 90% of all kidney malignancies and 30% of people with RCC have developed metastasis at the time of diagnosis. Based on European Association of Urology (EAU) guideline, therapy for metastatic RCC (mRCC) patient who cannot tolerate immune checkpoint inhibitor is pazopanib or sunitinib. However, these drugs cause several uncomfortable side effects for the patient. Therefore, this meta-analysis was made, based on the available evidence base, to compare the safety of pazopanib and sunitinib as the treatment of mRCC. Systematic reviews were made in accordance with the PRISMA guideline requirements, a literature review was conducted in January 2022 used PubMed, ScienceDirect, Cochrane Library, publishing year of at least 10 years with an adult population. And the data is analyzed using RevMan V.5.4. In total 1.665 participants, there were 431 patients taking pazopanib and 1.234 patients taking sunitinib from 8 studies. The result shows that sunitinib has more frequent result of side effects than pazopanib in several occasion like hand-foot syndrome, nausea/vomiting, skin rash, stomatitis &amp; mucosal inflammation, leucopenia and thrombocytopenia. Meanwhile, there are no significant differences between pazopanib and sunitinib in causing other side effect such as fatigue, diarrhea, hypertension, anemia, and increased liver enzymes. The conclusion is that pazopanib is better and has less frequent side effects than sunitinib.

The tumor-repressing effect of CYP27A1 on renal cell carcinoma by 27-HC arising from cholesterol metabolism.

As a key approach to mediate cholesterol metabolism, the role of the CYP27A1/27-HC axis in renal cell carcinoma (RCC) remains unclear. Analysis of CYP27A1 expression from public databases and metastatic cases in our center suggested that CYP27A1 was obviously downregulated in RCC tissues, and survival analysis further showed its correlation with favorable clinicopathological features and prognosis. In vitro, up and downregulation of CYP27A1 expression in RCC cell lines could definitely illustrate its anticipation involving apoptosis, proliferation, invasion, migration, and clonality. This could be achieved through upregulation of 27-HC concentration, which mediates the activation of signaling pathways of apoptosis and cell cycle arrest. Further, recovery of CYP27A1 expression could definitely inhibit the proliferation of RCC tumors in vivo. This is the first study to explore the role of the CYP27A1/27-HC axis in RCC. Attempts to maintain the normal function of the axis may be a potential strategy in the treatment of RCC, and the predictive value of CYP27A1 detection on the efficacy of targeted therapy in metastatic RCC is also worthy of attention.

Comparison of First-Line Anti-PD-1-Based Combination Therapies in Metastatic Renal-Cell Carcinoma: Real-World Experiences from a Retrospective, Multi-Institutional Cohort

Introduction: The aim of this study was to test for differences in overall (OS) and progression-free survival (PFS) rates and toxicity in first-line immune checkpoint inhibition (IO) combination therapy in metastatic renal-cell carcinoma (mRCC) patients. Methods: Between November 2017 and April 2021, 104 patients with histologically confirmed mRCC from 6 tertiary referral centers with either IO + IO (nivolumab + ipilimumab, n = 68) or IO + tyrosine kinase inhibitor (TKI) (pembrolizumab + axitinib, n = 36) were included. Kaplan-Meier and Cox regression analyses tested for OS and PFS differences. Results: Of 104 mRCC patients, 68 received IO + IO (65.4%) and 36 IO + TKI (34.6%) therapy, respectively. Median age was 67 years (interquartile range: 57–70.3). Patients receiving IO + TKI were less likely to be poor risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium score (16.7 vs. 30.9%) and presented with lower T-stage, compared to IO + IO treated patients. Median PFS was 9.8 months (CI: 5.3–17.6) versus 12.3 months (CI: 7.7 – not reached) for IO + IO versus IO + TKI treatment, respectively (p = 0.22). Median OS was not reached, survival rates at 12 months being 73.9 versus 90.0% for IO + IO versus IO + TKI patients (p = 0.089). In subgroup analyses of elderly patients (≥70 years, n = 38), IO + TKI treatment resulted in better OS rates at 12 months compared to IO + IO (91.0 vs. 57.0%; p = 0.042). Conclusion: IO + IO and IO + TKI as first-line therapies in mRCC patients were both comparable as for the oncological outcome and toxicity.

DNA damage repair (DDR) pathway alteration in advanced renal cell carcinoma (RCC) is association with good progression-free survival with tyrosine kinase inhibitor (TKI) therapy.

346 Background: Alterations in DNA damage repair (DDR) genes are associated with human tumorigenesis and may be as potential biomarkers for vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy in renal cell carcinoma. However, biologic significance and relevance to TKI targeted therapy in metastatic RCC are unknown. Methods: Genomic data and treatment outcomes were retrospectively collected for patients with metastatic RCC. Tumor and germline DNA were subject to targeted next generation sequencing across 642 genes of interest, including 60 DDR genes. Patients were dichotomized according to underlying DDR gene alteration into (1) DDR gene alterations present (Mut DDR); (2) wildtype (WT) DDR gene alterations present (WT DDR). Association between DDR status and therapeutic benefit was investigated separately for and vascular endothelial growth factor (VEGF) tyrosine kinase inhibitor (TKI) therapy. Results: Mut DDR were detected in 17/40 patients (42.5%). The most frequently DDR altered genes were TP53. For patients with TKI treatment, Mut DDR status was associated with superior progression free survival (log-rank p = 0.048), but not with superior overall survival (log-rank p = 0.39); after adjusting for International Metastatic Renal Cell Carcinoma Database Consortium risks and extent of prior therapy, the HR for Mut DDR was 2.68 (95% CI: 0.96–7.46; p = 0.059). Conclusions: DDR alterations are recurrent genomic events in patients with advanced RCC and were mostly clonal in this cohort. Dysfunction events in these genes may affect outcome with TKI therapy in adanced RCC, and these hypothesis-generating results deserve further study.

Pembrolizumab plus axitinib and nivolumab plus ipilimumab as first-line treatments of advanced intermediate- or poor-risk renal-cell carcinoma: a number needed to treat analysis from the Brazilian private perspective

Background Considering clinical benefits of new combination therapies for metastatic renal-cell carcinoma (mRCC), this study aims to calculate the number needed to treat (NTT) and the cost of preventing an event (COPE) for pembrolizumab plus axitinib (P + A), and nivolumab plus ipilimumab (N + I) as first-line treatments, from the Brazilian private perspective. Methods Overall survival (OS) and progression-free survival (PFS) data for intermediate- and poor-risk groups were obtained from KEYNOTE-426 and CHECKMATE-214 trials for P + A and N + I, respectively, versus sunitinib as mRCC first-line treatment. Results Considering a 12-month time horizon, 6 patients should be treated with P + A to prevent one death with sunitinib use, resulting in a COPE of 3,893,903 BRL. Using N + I, NNT for 12-month OS rate was 13 compared to sunitinib, with a COPE of 6,357,965 BRL. Regarding PFS data, NNT was also 6 when comparing P + A versus sunitinib, with an estimated COPE of 3,893,903 BRL. Estimated NNT was 20 comparing N + I and sunitinib, resulting in a COPE of 10,172,744 BRL. Cost differences between two treatment options, reached more than 6 million BRL for PFS, and 2 million BRL for OS. Conclusion At the 12-month landmark, P + A suggests better economic scenario versus N + I as first-line mRCC treatment option for intermediate- and poor-risk groups, through an indirect comparison using sunitinib as a common comparator.

Comparison of nivolumab plus ipilimumab with tyrosine kinase inhibitors as first-line therapies for metastatic renal-cell carcinoma: a multicenter retrospective study.

This study compared real-world outcomes of metastatic renal-cell carcinoma (mRCC) patients treated with tyrosine kinase inhibitors or nivolumab plus ipilimumab. Using the International mRCC Database Consortium (IMDC), we retrospectively evaluated intermediate- and poor-risk mRCC patients who were treated with nivolumab plus ipilimumab (Nivo-Ipi), tyrosine kinase inhibitors (TKIs) as the first-line therapy between August 2015 and January 2020. We compared oncological outcomes between the Nivo-Ipi group and TKIs group using multivariate logistic regression analysis with the inverse probability of treatment weighting (IPTW) method. In this study 278 patients were included. There were 52 and 226 patients in the Nivo-Ipi and TKIs groups (sunitinib 97, axitinib 118, sorafenib 9, pazopanib 2), respectively. The median age in the Nivo-Ipi and TKIs groups were 69and 67years, respectively. There was no significant difference in age, performance status, history of nephrectomy, and the IMDC risk group distribution between the groups. The objective response rate was significantly higher in the Nivo-Ipi group (38%) than in the TKIs group (23%, P = 0.018). The IPTW-adjusted Cox regression analysis showed that a significantly longer progression-free survival (hazard ratio 0.60, P = 0.039) and overall survival (hazard ratio 0.51, P = 0.037) rates in the Nivo-Ipi group than those in the TKIs group. The oncological outcomes of patients receiving the first-line therapy of nivolumab plus ipilimumab in real-world practice were significantly improved in comparison with first-line TKIs therapy.

Application of IMDC criteria across first-line (1L) and second-line (2L) therapies in metastatic renal-cell carcinoma (mRCC): New and updated benchmarks of clinical outcomes.

5063 Background: In patients with mRCC, the International mRCC Database Consortium (IMDC) criteria have been validated as a prognostic tool in patients treated with targeted therapy in the 1-4L settings and with 2L Nivolumab (Nivo). However, it is unknown whether the IMDC criteria can be used to risk stratify in recently approved 1L IO combination therapies, including Ipilimumab + Nivolumab (IOIO) and Axitinib + Pembrolizumab/Avelumab (IOVE). We sought to assess the ability of the IMDC criteria to risk stratify with the use of novel 1L IO combinations and provide updated benchmarks for older 1L and 2L treatments. Methods: Patients with mRCC starting systemic therapy between 2010-2019 were identified through the IMDC. IMDC risk score was calculated at the time of starting the line of therapy of interest. The primary endpoint was overall survival (OS) from time of initiating the treatment of interest. Results: From a total of 6596 unique patients, 5043 treated in the 1L setting and 2498 treated in the 2L setting were included in the analysis. Across the entire cohort, median age was 61, 73% were male, 16% had sarcomatoid features, 79% underwent nephrectomy and 88% had clear-cell histology. IMDC risk groups for 1L and 2L treatment were 17%, 57%, 27% and 10%, 60%, 30% for favourable-, intermediate- and poor-risk disease, respectively. IMDC criteria appropriately risk stratified into 3 prognostic groups in 1L IOIO and 1L IOVE combinations, in addition to older treatments: 1L VEGF TT, 2L VEGF TT, 2L Nivo and 2L Everolimus. Results are displayed in Table. Due to the novelty of 1L IO combinations, median follow up time was shorter and thus landmark OS values are presented. Conclusions: IMDC criteria may be used to risk stratify in recently approved 1L IO combination therapies in addition to older 1L and 2L treatments. These data provide contemporary benchmarks for OS that may be used for patient counseling and trial design. [Table: see text]

PCN69 THE COMPARATIVE PHARMACOECONOMIC ANALYSIS OF USING DIFFERENT TARGET DRUGS FOR SECOND-LINE THERAPY OF METASTATIC RENAL CELL CARCINOMA IN RUSSIA

Renal cell carcinoma (RCC) is one of the most costly oncological diseases in Russia due to introduction into clinical practice of new targeted drugs that have higher efficacy and cost. The main aim of this study was to perform cost-effectiveness analysis of using axitinib as second-line therapy in metastatic RCC (mRCC) in adult patients. Analysis of the published clinical trials was conducted to evaluate comparative efficacy and safety of using different types of second-line therapy used in Russia – axitinib, everolimus and sorafenib. MS Excel based Markov model of medical care patients with mRCC has been developed. Markov model included three states: without progression, progression and death. Time horizon was 10 years, cycle length was 1 month. To measure costs of mRCC treatment with different types of second-line therapy for the state budget were used “cost-effectiveness” analysis (CEA). Direct medical costs included drugs, therapy monitoring, inpatient, side effects correction, palliative care and were calculated from the Russian healthcare system perspective. The progression free survival (PFS) was included into the model as the effectiveness criteria. The total direct medical costs of treatment mRCC per patient were $15823 with sorafenib, $19959 with axitinib, $20819 with everolimus. The CEA has shown that in comparison with sorafenib ICER for axitinib was $26688 and for everolimus - $150562 per 1 year PFS. The difference amounted to 82% in favor of axitinib (rate for June 2019). Using axitinib as second-line therapy in mRCC in adult patients was effective and economically justified treatment option in Russia.

First-line Immuno-Oncology Combination Therapies in Metastatic Renal-cell Carcinoma: Results from the International Metastatic Renal-cell Carcinoma Database Consortium

BackgroundIn metastatic renal-cell carcinoma (mRCC), recent data have shown efficacy of first-line ipilimumab and nivolumab (ipi-nivo) as well as immuno-oncology (IO)/vascular endothelial growth factor (VEGF) inhibitor combinations. Comparative data between these strategies are limited. ObjectiveTo compare the efficacy of ipi-nivo versus IO-VEGF (IOVE) combinations in mRCC, and describe practice patterns and effectiveness of second-line therapies. Design, setting, and participantsUsing the International Metastatic Renal-cell Carcinoma Database Consortium (IMDC) dataset, patients treated with any first-line IOVE combination were compared with those treated with ipi-nivo. InterventionAll patients received first-line IO combination therapies. Outcome measurements and statistical analysisFirst- and second-line response rates, time to treatment failure (TTF), time to next treatment (TNT), and overall survival (OS) were analysed. Hazard ratios were adjusted for IMDC risk factors. Results and limitationsIn total, 113 patients received IOVE combinations and 75 received ipi-nivo. For IOVE combinations versus ipi-nivo, first-line response rates were 33% versus 40% (between-group difference 7%, 95% confidence interval [CI] –8% to 22%, p = 0.4), TTF was 14.3 versus 10.2 mo (p = 0.2), TNT was 19.7 versus 17.9 mo (p = 0.4), and median OS was immature but not statistically different (p = 0.17). Adjusted hazard ratios for TTF, TNT, and OS were 0.71 (95% CI 0.46–1.12, p = 0.14), 0.65 (95% CI 0.38–1.11, p = 0.11), and 1.74 (95% CI 0.82–3.68, p = 0.14), respectively. Sixty-four (34%) patients received second-line treatment. In patients receiving subsequent VEGF-based therapy, second-line response rates were lower in the IOVE cohort than in the ipi-nivo cohort (15% vs 45%; between-group difference 30%, 95% CI 3–57%, p = 0.04; n = 40), though second-line TTF was not significantly different (3.7 vs 5.4 mo; p = 0.4; n = 55). Limitations include the study’s retrospective design and sample size. ConclusionsThere were no significant differences in first-line outcomes between IOVE combinations and ipi-nivo. Most patients received VEGF-based therapy in the second line. In this group, second-line response rate was greater in patients who received ipi-nivo initially. Patient summaryThere were no significant differences in key first-line outcomes for patients with metastatic renal-cell carcinoma receiving immuno-oncology/vascular endothelial growth factor inhibitor combinations versus ipilimumab and nivolumab.

First-line (1L) immuno-oncology (IO) combination therapies in metastatic renal-cell carcinoma (mRCC): Results from the international mRCC database consortium (IMDC).

4577 Background: In mRCC, ipilimumab and nivolumab (ipi-nivo) is a 1L treatment option. Recent data have also shown efficacy of 1L IO-VEGF (IOVE) inhibitor combinations. Comparative data between these two strategies are limited and the efficacy of subsequent therapies remains unknown. Methods: Using the IMDC dataset, patients (pts) treated with any 1L IOVE combination were compared to those treated with ipi-nivo. Multivariable Cox regression analysis was performed to control for imbalances in IMDC risk factors. Results: 188 pts received 1L IO combination therapy: 113 treated with IOVE combinations and 75 with ipi-nivo. Baseline characteristics and IMDC risk factors were comparable between groups. When comparing IOVE combinations vs ipi-nivo, 1L response rate (RR) was 33% vs 40% (p=0.39), time to treatment failure (TTF) was 14.3 (95% CI 9.2-16.1) vs 10.2 months (95% CI 6.7-15.1, p=0.23), and median overall survival (OS) was not reached (NR) (95% CI 22.3-NR) vs NR (95% CI 35.1-NR, p=0.17). When adjusted for IMDC risk factors, the hazard ratio (HR) for TTF was 0.71 (95% CI 0.46-1.12, p=0.14) and the HR for death was 1.74 (95% CI 0.82-3.68, p=0.14). Second-line (2L) treatments were varied. In pts receiving subsequent VEGF-based therapy, 2L RR was lower in the IOVE (n=20) versus ipi-nivo (n=20) cohort (15% vs 45%; p=0.04), though 2L TTF was not significantly different (3.7 vs 5.4 months, p=0.40, n=55). The use of IO post IOVE was uncommon and 3/5 pts had PD as best response; 2/5 had PR/SD but their 1L IOVE exposure was short at &lt;3 months. Conclusions: There does not appear to be a superior 1L IO combination strategy in mRCC, as lOVE combinations and ipi-nivo have comparable 1L RR, TTF and OS. Most pts received VEGF-based therapy in the 2L. In this group, 2L RR was greater in pts who received ipi-nivo, though there was no difference in 2L TTF. [Table: see text]

Immunotherapy Is Changing First-Line Treatment of Metastatic Renal-Cell Carcinoma.

The incidence of renal-cell carcinoma has been increasing each year, with nearly one third of new cases diagnosed at advanced or metastatic stage. The advent of targeted therapies for metastatic renal-cell carcinoma (mRCC) has underscored the need to subtype tumors according to tumor-immune expression profiles that may more reliably predict treatment outcomes. Over the past 2 decades, several vascular endothelial growth factor (VEGF) and tyrosine kinase inhibitors have been the mainstay for first- and second-line treatment of mRCC. Very recently, immunotherapy checkpoint inhibitors have significantly changed the treatment landscape for patients with mRCC, particularly for first-line treatment of intermediate to poor risk mRCC patients. Now, combination immunotherapy as well as combinations of immunotherapy with targeted agents can significantly alter disease outcomes. The field of immuno-oncology for mRCC has unveiled a deeper understanding of the immunoreactivity inherent to these tumors, and as a result combination therapy is evolving as a first-line modality. This review provides a timeline of advances and controversies in first-line treatment of mRCC, describes recent advances in understanding the immunoreactivity of these tumors, and addresses the future of combination anti-VEGF and immunotherapeutic platforms.

Immunotherapy-based combinations: an update.

The advent of immunotherapy significantly improved clinical outcomes in cancer patients, although immune checkpoint blockade (ICB) still lack of efficacy in a consistent proportion of treated patients. The purpose of this article is to review the most innovative and clinically promising ICB-based combinations designed to improve the efficacy of cancer immunotherapy. First-line combinatorial treatment with ipilimumab and nivolumab has recently shown to be superior to the standard of care in a subset of metastatic nonsmall cell lung cancer (NSCLC) and renal cell carcinoma (RCC). The combination of programmed cell death protein 1 (PD-1)/PD-L1 blockade with antiangiogenics has demonstrated a consistent clinical efficacy, especially for the combination of bevacizumab and atezolizumab as first-line therapy in metastatic RCC. The sequential combination of definitive chemoradiotherapy followed by durvalumab maintenance in advanced, unresectable NSCLC became the new standard of care, while the addition of pembrolizumab to first-line chemotherapy in metastatic NSCLC significantly improves overall survival. Despite promising results for the combination of ICBs with v-raf murine sarcoma viral oncogene homolog B/MAPK/ERK kinase inhibitors or epidermal growth factor receptor inhibitors, especially in melanoma and NSCLC, safety concerns slowed down the development of such strategies. Immunotherapy-based combinations are becoming the standard of care for cancer treatment, in particularly for advanced melanoma, NSCLC and RCC.

Nivolumab in the treatment of advanced renal cell carcinoma.

Renal cell carcinoma (RCC) has typically been considered an immunogenic malignancy with responses seen to IL-2 and IFN-α. Response rates, however, were low and at the cost of considerable toxicity and as such, agents targeting angiogenesis have become the mainstay of treatment. Nivolumab is an immune checkpoint inhibitor targeting PD-1 thereby upregulating the host immune response against tumor cells. Nivolumab has emerged as a promising new therapy in advanced malignancies, and the first agent to show survival advantage in patients failing prior VEGFR-targeted therapy in metastatic RCC. This review summarizes the present evidence, toxicity profile, potential predictive biomarkers and promising future strategies with nivolumab in metastatic RCC.

Pazopanib with low fat meal (PALM) in advanced renal cell carcinoma (RCC).

683 Background: Pazopanib, a highly lipophilic standard first-line therapy for metastatic RCC, is conventionally taken in a fasting state but has significant gastrointestinal toxicities and 96% of ingested drug is fecally excreted, with major financial implications. Single dose studies with fat meals suggested bioavailability is increased two-fold. We sought to evaluate toxicity/safety, bioavailability and anti-tumor efficacy of daily pazopanib taken with a low fat meal over 12 weeks. Methods: Enrolled pts had unresectable locally advanced or metastatic RCC with clear cell component, RECIST 1.1 measurable disease, ECOG PS ≤2, adequate organ function, and up to 3 prior therapies including VEGF(R) and checkpoint inhibitors. Subjects took pazopanib, starting dose of 400 mg, once daily with low-fat meal ( &lt; 400 cal with &lt; 20% fat/10 g of fat) in 2 wk cycles with MD discretion to dose-escalate q2wks up to 800 mg or irreversibly dose-reduce as low as 200 mg based on tolerance/toxicity for 12 wks. Baseline and end of study echocardiograms, and triplicate ECGs at each cycle start were monitored. Home pill diaries were collected. PK was analyzed in the first 3 cycles. Results: Sixteen pts were accrued: median age 60 (range: 47 – 75),75% men,11 were ECOG PS 0. Most (12/16) subjects with no prior therapy, 13/16 had intermittent Heng risk criteria, 3 favorable; 5 sarcomatoid component. Diet compliance by pill diary was outstanding, except for 1 pt for 1 cycle. Calculated mean daily dose was 535 mg (153-750 mg). Therapy was well tolerated; 5 Grade 3 AEs (1 HTN, 1 chest pain, 2 AST/ALT elevations, 1 Abd pain) occurred. LVEF declined by &gt; 15% in 3 pts but none to &lt; 50%. QTc prolongation &gt; 450 ms did not occur. All but 3 pts completed protocol (off d/t toxicity-HTN, LFTs, chest pain). ORR was PR 5 (31%); SD 7 (44%). PK data and pharmacogenomics CYP3A4 polymorphism data correlated with toxicity. Conclusions: Pazopanib taken with a low fat meal appears to be better tolerated compared to published data on empty stomach administration, especially with fewer GI toxicities, including diarrhea. It also resulted in comparable efficacy with fewer cumulative pills over the 12-week period, with substantial cost implications. Larger trials of pazopanib with low fat meal are warranted. Clinical trial information: NCT02729194.

Patients perspectives on adjuvant therapy in renal cell carcinoma.

644 Background: At this point in time, there is no approved adjuvant therapy (AT) for renal cell carcinoma (RCC) . The discussion on AT is driven by the pending maturation of overall survival (OS) data for sunitinib in patients at high risk for recurrence. Data on patient´s perception of AT are missing. The purpose of this study was to assess the value of specific adjuvant outcome measures to patients with RCC. Methods: We conducted a survey-monkey survey in n=450 patients with RCC on the perspective on AT. The survey was promoted via kccure.org, facebook and smartpatients.com. Question were not related to specific results of adjuvant trials but asking only about the attitude towards AT as an intervention. Results: Median age was 55.6 years (17-82 years) and 56.4% of the patients were female. 73.6% of the patients underwent nephrectomy as primary therapy, while 22.0% had a partial nephrectomy. 76.4% of the patients had clear cell RCC. 39.1% had recurrence of RCC and 35.3% were receiving systemic therapy for metastatic RCC. 63.1% of patients would use AT if it prolonged OS, followed by 60.1% if AT prolonged disease free survival (DFS), 42.7% if AT demonstrated acceptable toxicity, and 36.7% if guaranteed insurance coverage and efficacy. Experience with systemic therapy was correlated with a wish for a prolonged OS (p&lt;0.0001). Patients with a history of systemic therapy rely on the physician’s recommendation in contrast to patients without a history of systemic therapy (p&lt;0.0001). The recurrence status, age, initial stage and type of surgery had no influence on the patients´ decisions. 28.0% of the patients would need more information prior to their decision, 24.2% would only take AT with a proven OS benefit, 16.9% would use AT if there was moderate toxicity, 13.6% would use AT independent of the associated toxicity level, 8.2% would only use AT without any toxicity. 3.8% of the patients would not use AT. Patients on systemic therapy had a significant higher acceptance of toxicity (p&lt;0.0001). Conclusions: Patients are willing to use AT to achieve OS and DFS benefits, and place lower emphasis on toxicity. These data provide an important perspective on patient perceptions of AT, and emphasize the need for patient education on harms and benefits of AT.

Drug Holiday in Metastatic Renal-Cell Carcinoma Patients Treated With Vascular Endothelial Growth Factor Receptor Inhibitors.

Tyrosine kinase inhibitor (TKI) therapy in metastatic renal-cell carcinoma (mRCC) is noncurative and may be associated with significant toxicities. Some patients may receive treatment breaks as a result of TKI-related adverse effects or planned drug holidays. In this retrospective study, mRCC patients who underwent drug holidays during TKI therapy at 2 different institutions were analyzed. A drug holiday was defined as a period of drug cessation for≥ 3 months for reasons other than progressive disease. Of the 112 patients, the median duration of the first drug holiday for the overall cohort was 16.8 months (95% confidence interval, 12.5-26.4), and 40 patients (36%) remain on the first drug holiday. Overall, patients received a median of 2 lines of treatment. Complete response before the initial drug holiday (n= 14) was associated with a longer surveillance period (P=.0004). The observed median survival of this cohort was 71.7 months (range, 1.3 to 93+ months). Some selected mRCC patients with a favorable response to TKIs may be eligible for drug holidays. The cohort evaluated in this retrospective study represents a highly selected group of patients with indolent disease biology.

The current status of immunobased therapies for metastatic renal-cell carcinoma.

The management of metastatic renal-cell carcinoma (mRCC) represents an important clinical challenge. Since being approved in the early 1990s, aspecific immunotherapy has been a mainstay of treatment for mRCC and the only therapy that has demonstrated long-term cures for mRCC. However, in recent times there have been landmark advances made in the field of specific immunotherapy for a number of malignancies, including kidney cancer. This review outlines the range of immunobased agents currently available for the treatment of mRCC.

Role of fibroblast growth factor receptor in sunitinib-resistant renal cell carcinoma

In renal cell carcinoma (RCC), surgical therapy remains to be the only curative approach for patients with localised kidney tumor, with recurrence rates as high as 40% in high risk patients. As well, even though there are now many approved therapies for metastatic RCC (mRCC), resistance eventually develops and is fatal for metastatic patients. Tyrosine kinase inhibitors (TKIs) that target the VEGF pathway are considered first-line therapy for clear cell RCC, the most common type of RCC.

Abstract CT083: Clinical activity, immune and molecular correlates of nivolumab vs. nivolumab plus bevacizumab vs nivolumab plus ipilimumab in metastatic renal cell carcinoma

Abstract Background: Immune checkpoint blockade including anti-CTLA-4 (ipilimumab, BMS) and anti-PD1 (nivolumab, BMS) as monotherapies have been known to have clinical activity against metastatic renal cell carcinoma (MRCC), but with relatively low clinical response rate (10-25%). Anti-VEGF antibody bevacizumab is a standard therapy for MRCC also with a low response rate (&amp;lt;20%). Since anti-PD1 and anti-CTLA-4 use distinct mechanisms for T cell activation and bevacizumab can promote the function of antigen presenting cells, we hypothesize that combination therapy with nivolumab + bevacizumab or nivolumab + ipilimumab will lead to measurable immunological changes and improved clinical activity. Methods: In this open-label, pilot, pre-surgical/pre-biopsy trial (NCT02210117), adults with MRCC without prior immune checkpoint therapy and anti-VGEF therapy were enrolled, stratified by planned surgical procedure, and randomized 1:2:1 to receive nivolumab monotherapy, nivolumab + bevacizumab or nivolumab + ipilimumab, followed by cytoreductive nephrectomy, metastasectomy, or post-treatment biopsy, and subsequent maintenance therapy with nivolumab for up to 2 years until disease progression and intolerable toxicity. Pre- and post-treatment blood and tumor samples were obtained for dynamic monitoring of immune and molecular correlates to clinical activity. Results: Sixty patients were treated (median duration 17.1 weeks, range 2.74 to 85.1 weeks as of 12/6/16). Fourty-four were evaluable for clinical responses post-procedures. Five of 12 (42%) nivolumab monotherapy treated patients had partial response (PR), 4 (33%) had stable disease (SD), and 3 (25%) had progression of disease (PD) and 0 withdrew early (W). In the nivolumab + bevacizumab arm, 1 of 19 (5%) had complete response and 9 (47%) patients had PR, for a response rate of 53%, 3 (16%) had SD, 3 (16%) with PD and 3 (16%) W. In the nivolumab + ipilimumab arm, 5 of 13 (38%) patients had PR, 1 (8%) had SD and 5 (38%) had PD and 2 (15%) W. Treatment was generally well tolerated with mostly grade 1 or 2 adverse events. Grade 3 or higher toxicities were 19% in the nivolumab arm, 41% in the nivolumab + bevacizumab arm (including 17% bevacizumab-specific hypertension that was well controlled by anti-hypertensive medications), and 27% in the nivolumab + ipilimumab arm. Correlative laboratory studies including flow cytometry, IHC, and gene profiling analysis identified a number of immune gene signatures including an IFN-γ gene signature that we will report in more details. Conclusions: Combination therapy with nivolumab + bevacizumab and nivolumab + ipilimumab showed promising clinical activities in patients with MRCC. Immune and molecular correlative studies may allow us to identify novel biomarkers that can be used for correlation with clinical outcomes in patients with MRCC. Citation Format: Jianjun Gao, Jose A. Karam, Christopher G. Wood, Surena Matin, Kamran Ahrar, Eric Jonasch, Nizar Tannir, Matthew Campell, Chaan S. Ng, Rebecca S. Slack, Priya Rao, James P. Allison, Jorge M. Blando, Luis M. Vence, Sreyashi Basu, Hao Zhao, Tenghui Chen, Hong Chen, Padmanee Sharma. Clinical activity, immune and molecular correlates of nivolumab vs. nivolumab plus bevacizumab vs nivolumab plus ipilimumab in metastatic renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT083. doi:10.1158/1538-7445.AM2017-CT083